The present invention relates to processes for preparing cilostazol.
The present invention pertains to processes for preparing 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone of formula (I) 
which is also known by the generic name cilostazol. Cilostazol inhibits cell platelet aggregation and is used to treat patients with intermittent claudication.
Cilostazol is described in U.S. Pat. No. 4,277,479 (xe2x80x9cthe ""479 patentxe2x80x9d), which teaches a preparation wherein the phenol group of 6-hydroxy-3,4-dihydroquinolinone (xe2x80x9c6-HQxe2x80x9d) of formula (II) is alkylated with a 1-cyclohexyl-5-(4-halobutyl)-tetrazole (xe2x80x9cthe tetrazolexe2x80x9d) of formula (III). It is recommended to use an equimolar or excess amount up to two molar equivalents of the tetrazole (III). 
The ""479 patent mentions a wide variety of bases that may be used to promote the alkylation reaction, namely, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate, elemental sodium, elemental potassium, sodium methylate, sodium ethylate, triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diaza-bicyclo[4,3,0]-non-5-ene, 1,5-diaza-bicyclo[5,4,0]-undec-7-ene (xe2x80x9cDBUxe2x80x9d), and 1,4-diazabicyclo[2,2,2]octane.
The ""479 patent states that the alkylation may be conducted neat or in solvent. Suitable solvents are said to be methanol, ethanol, propanol, butanol, ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methylethylketone, benzene, toluene, xylene, methyl acetate, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoryl triamide.
According to Examples 4 and 26 of the ""479 patent, cilostazol was prepared using DBU as base and ethanol as solvent.
In Nishi, T. et al. Chem. Pharm. Bull. 1983, 31, 1151-57, a preparation of cilostazol is described wherein 6-HQ is reacted with 1.2 molar equivalents of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetraazole (xe2x80x9cCHCBT,xe2x80x9d tetrazole III wherein Xxe2x95x90Cl) in isopropanol with potassium hydroxide as base. Cilostazol was obtained in 74% yield.
One reason for using an excess of tetrazole as was done in Nishi et al. and recommended by the ""479 patent is that CHCBT is unstable to some bases. When exposed to an alkali metal hydroxide in water for a sufficient period, CHCBT undergoes elimination and cyclization to yield byproducts (IV) and (V). 
Nishi et al.""s reported yield is based upon the limiting reagent 6-HQ. The yield with respect to CHCBT is 69%. In the economics of producing a chemical on a large scale, improvements in chemical yield are rewarded with savings in the chemical""s production cost. CHCBT is an expensive compound to prepare and should not be wasted. It would be highly desirable to be able to realize further improvement in yield of the alkylation of 6-HQ with CHCBT and its halogen analogs in a way that lowers the cost of producing cilostazol. In other words, it would be desirable to further improve the yield of cilostazol by increasing the degree of conversion of CHCBT to cilostazol, as opposed to, for example, improving the yield calculated from 6-HQ by increasing the excess of tetrazole or manipulating the reaction conditions in a way that increases the conversion of 6-HQ to cilostazol but at the expense of poorer conversion of CHCBT to cilostazol.
Although CHCBT is unstable to hydroxide ion, it is relatively stable in the presence of non-nucleophilic organic bases. There are advantages to using inorganic bases, however, that favor their selection over organic bases. Firstly, the phenolic proton of 6-HQ is labile. Thus, relatively non-caustic and easily handled inorganic bases may be used to prepare cilostazol. Further, inorganic bases are easier to separate from the product and are less toxic to the environment when disposed than organic bases are. Therefore, it would also be highly desirable to use an inorganic base while realizing an improvement in conversion of CHCBT to cilostazol.
The present invention provides improved processes for preparing cilostazol (I) by alkylating the phenol group of 6-HQ with the xcex4 carbon of a 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole.
In a first aspect, the invention provides a process wherein 6-HQ and a water soluble base are dissolved in water. A 1-cyclohexyl-5-(4-halobutyl)-tetrazole is dissolved in a water-immiscible organic solvent. The two solutions are combined in the presence of a quaternary ammonium salt phase transfer catalyst to form a biphasic mixture in which the 6-HQ and tetrazole react to produce cilostazol. The purity of the cilostazol may be detected by reversed-phase high performance liquid chromatography (HPLC) using gradient elution. The process may be practiced by a variety of procedures taught by the present invention. In one variation, a reaction promoter, like sodium sulfate, is added to accelerate phase transfer of 6-HQ into the organic solvent.
Another aspect of the present invention provides a preparation of cilostazol from a single phase reaction mixture of 6-HQ and a 1-cyclohexyl-5-(4-halobutyl)-tetrazole and a mixture of inorganic bases. The base mixture comprises an alkali metal hydroxide and alkali metal carbonate. This process minimizes decomposition of the starting tetrazole and cilostazol by buffering the pH which results in improved yield calculated based upon the tetrazole, the more precious of the two organic starting materials. A preferred embodiment wherein the alkali metal hydroxide is added portionwise minimizes the formation of dimeric byproducts. In another preferred embodiment of the homogeneous process, the reaction mixture is dehydrated with molecular sieves before the tetrazole is added.
Yet another aspect of the present invention provides a pharmaceutical composition comprising substantially pure cilostazol obtained by the methods of the present invention described above. By xe2x80x9csubstantially purexe2x80x9d is meant having a purity equal to or greater than 98%.
Another aspect of the present invention provides a pharmaceutical composition comprising cilostazol particles of reduced particle size. By xe2x80x9creduced particle sizexe2x80x9d is meant about 90% of the particles having a diameter equal to or less than about 60 microns (d(0.9)xe2x89xa660 microns). The reduced particle size may be obtained by fine-milling or micronization.